This is the first competing continuation for the multi-site Midwest Alcoholism Research Center (MARC). The broad focus of our research is the etiology and course of alcohol problems and associated comorbidity in community (rather than clinically ascertained) samples, with an emphasis on prospective high-risk, behavioral and molecular genetic, genetic epidemiologic and experimental perspectives, and with a particular focus on adolescents and youth. The MARC is organized as: (i) an Administrative Core, under the leadership of MARC Director Heath and Scientific and Administrative Co-Directors Sher and Bucholz, which is responsible for coordinating MARC-based research projects with each other, and with our broader R01-supported Portfolio of genetic, prospective high-risk and human experimental studies, as well as for assessment, ascertainment, data-management and methodologic support for MARC-based research projects; (ii) four research studies; and (iii) a pilot to facilitate the development of new alcohol researchers, as well as new directions for established investigators. The research studies include four parts. First, investigating in the human experimental laboratory interactive effects of alcohol and tobacco on measures of sensitivity to alcohol effects (postural instability) or tobacco effects (physiologic tremor). Second, using a children-of-twins paradigm to investigate the effects of environmental consequences of maternal alcoholism, including effects that may interact with offspring genotype, by contrasting outcomes in offspring 7 years and older who are either offspring of an alcoholic mother (at high genetic risk, and high environmental risk), or of an unaffected mother who may have (a) a monozygotic twin sister who is alcoholic (also high genetic risk, but reduced environmental risk), or (b) an alcoholic dizygotic twin sister (intermediate genetic risk, reduced environmental risk), or (c) an unaffected twin sister (low genetic and low environmental risk). Third, extending 4 ongoing studies that have followed samples prospectively from adolescence into young adulthood, by adding a molecular genetic component, to investigate the developmental unfolding of candidate gene effects on risk. Fourth, seeking to bridge the gap between epidemiologic and genetic epidemiologic studies of alcohol-tobacco comorbidity, and human experimental studies, as an ecological study of the co-occurrence of alcohol and tobacco use and their motivational sequelae, assessed by electronic diary. Together these are integrated by our desire to advance etiological research on genotype x environment interaction effects on alcoholism risk at multiple levels of analysis.